Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 01 April 2018

Indication(s)

1 INDICATIONS AND USAGE SIGNIFOR LAR is a somatostatin analog indicated for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option. (1.1) 1.1 Acromegaly SIGNIFOR LAR is a somatostatin analog indicated for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option.

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Advisory information

contraindications
4 CONTRAINDICATIONS None. None. (4)
Adverse reactions
6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: Hyperglycemia and Diabetes [see Warnings and Precautions (5.1)] Bradycardia and QT Prolongation [see Warnings and Precautions (5.2)] Liver Test Elevations [see Warnings and Precautions (5.3)] Cholelithiasis [see Warnings and Precautions (5.4)] Pituitary Hormone Deficiency(ies) [see Warnings and Precautions (5.5)] Adverse drug reactions associated with SIGNIFOR LAR and occurring in ≥ 20% of patients were diarrhea, cholelithiasis, hyperglycemia, and diabetes mellitus. (6) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Drug-Naïve Patients with Acromegaly The data described in Table 1 are derived from an active-controlled trial in patients with acromegaly naïve to previous drug therapy [see Clinical Studies (14.1)]. The data reflect exposure of 178 patients with acromegaly to SIGNIFOR LAR for a mean duration of 43 weeks. In the overall study population, 52% were female and the average age of patients was 45 years. Additional information on design and demographics of this trial are described below [see Clinical Studies (14.1)]. Table 1 presents common adverse reactions associated with SIGNIFOR LAR. These adverse reactions were not present at baseline or, if present, worsened from baseline and occurred in at least 5% of patients treated with SIGNIFOR LAR. Table 1 - Adverse Reactions Occurring in ≥ 5% of Patients Exposed to SIGNIFOR LAR in Patients with Acromegaly Naïve to Drug Therapy *Diabetes mellitus includes the following PTs: Diabetes mellitus and type 2 diabetes mellitus **Sinus bradycardia includes the following PTs: Bradycardia and sinus bradycardia ***Injection site reaction related AEs includes the following PTs: Injection site pain, Injection site reaction, Injection site haematoma, Injection site pruritus, Injection site swelling, Injection site erythema Adverse Reaction Type SIGNIFOR LAR (40-60 mg) % N=178 Active Comparator % N=180 Hyperglycemia Related Adverse Reactions Hyperglycemia 29 8 Diabetes mellitus* 26 4 Blood glucose increased 8 2 Glycosylated hemoglobin increased 6 2 Hypoglycemia 5 7 Gastrointestinal Related Adverse Reactions Diarrhea 39 45 Abdominal pain 18 22 Nausea 14 22 Abdominal distension 12 12 Vomiting 8 7 Abdominal pain upper 6 8 Hepatobiliary Related Adverse Reactions Cholelithiasis 26 36 Cardiac Related Adverse Reactions Sinus bradycardia** 10 7 Hypertension 8 7 Nervous System Related Adverse Reactions Headache 19 26 Dizziness 10 11 Skin Related Adverse Reactions Alopecia 18 19 Infections Related Adverse Reactions Nasopharyngitis 16 16 Influenza 8 4 Upper respiratory tract infection 7 3 Cough 5 8 Laboratory Related Adverse Reactions Blood creatine phosphokinase increased 13 12 Alanine aminotransferase increased 8 4 Aspartate aminotransferase increased 6 4 Weight decreased 5 4 General and Injection Site Related Adverse Reactions Fatigue 10 10 Injection site reaction*** 7 7 Musculoskeletal and Connective Tissue Related Adverse Reactions Arthralgia 10 12 Back pain 8 11 Pain in extremity 7 4 Blood Related Adverse Reactions Anemia 6 6 Other notable adverse reactions which occurred with a frequency of 5% or less for SIGNIFOR LAR were: adrenal insufficiency (3%); glucose tolerance impaired (1%); QT-prolongation (4%); blood amylase increased (2%). Patients with Acromegaly Inadequately Controlled on other Somatostatin Analogs at Baseline The data described in Table 2 are derived from an active-controlled study in patients with acromegaly inadequately controlled at baseline on other somatostatin analogs [see Clinical Studies (14.2)]. These data reflect exposure of 63 and 62 patients to SIGNIFOR LAR 40 mg and 60 mg, respectively, for a mean duration of 24 weeks. In the overall study population, 56% were female and the average age of patients was 45 years. Additional information on design and demographics of this trial are described below [see Clinical Studies (14.1)]. Table 2 presents common adverse reactions associated with SIGNIFOR LAR. These common adverse reactions were not present at baseline or, if present, worsened from baseline and occurred in at least 5% of patients treated with SIGNIFOR LAR. Table 2 – Adverse Reactions Occurring in ≥ 5% of Patients Exposed to SIGNIFOR LAR in Patients with Acromegaly Previously Treated with Other Somatostatin Analogs * Diabetes mellitus includes the following PTs: diabetes mellitus and type 2 diabetes mellitus Adverse Drug Reactions SIGNIFOR LAR 40 mg % N=63 SIGNIFOR LAR 60 mg % N=62 Active Comparators % N=66 Hyperglycemia Related Adverse Reactions Hyperglycemia 33 30 14 Diabetes mellitus* 21 31 9 Blood glucose increased 5 7 0 Hypoglycemia 3 7 0 Gastrointestinal Related Adverse Reactions Diarrhea 16 19 5 Abdominal pain 8 8 3 Nausea 3 7 3 Hepatobiliary Related Adverse Reactions Cholelithiasis 10 13 14 Cardiac Related Adverse Reactions Atrioventricular block first degree 6 0 0 Nervous System Related Adverse Reactions Headache 14 3 5 Dizziness 8 2 3 Skin and Subcutaneous Tissue Related Adverse Reactions Alopecia 2 7 0 Infections Related Adverse Reactions Nasopharyngitis 6 11 3 Blood Related Adverse Reactions Anemia 6 3 3 Other notable adverse reactions which occurred with a frequency of 5% or less in the SIGNIFOR LAR 40 mg, SIGNIFOR LAR 60 mg arm, respectively, were adrenal insufficiency (2% and 0%) and glucose tolerance impaired (3% and 5%). Hyperglycemia The average fasting plasma glucose levels in patients with acromegaly naïve to drug therapy study [see Clinical Studies (14.1)] across visits is shown in Figure 2. Figure 2. Mean Fasting Plasma Glucose (mg/dL) by Visit in the Study of Patients with Acromegaly Naïve to Drug Therapy* *Numbers of patients with a glucose value at the given timepoint in the SIGNIFOR LAR/Active comparator arms are displayed as xxx/xxx on the x axis Pancreatic Enzyme Elevation and Pancreatitis Asymptomatic, elevations in lipase and alpha amylase were observed in 30% and 20% of patients receiving SIGNIFOR LAR in the drug naïve study [see Clinical Studies (14.1)] and in 1% and 3% of patients receiving SIGNIFOR LAR in the study of patients previously treated [see Clinical Studies (14.2)]. In the drug-naïve study, 2 patients receiving SIGNIFOR LAR developed pancreatitis. Pancreatitis is a potential adverse reaction associated with the use of SIGNIFOR LAR due to the association between cholelithiasis and acute pancreatitis. Figure 2. Mean Fasting Plasma Glucose (mg/dL) by Visit in the Study of Patients with Acromegaly Naïve to Drug Therapy*

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION The initial dose is 40 mg by intramuscular injection once every 4 weeks (every 28 days). (2.2) Adjust dose based on biochemical response and tolerability. (2.3) Evaluate fasting plasma glucose, hemoglobin A1c, liver enzyme tests, electrocardiogram (ECG), serum magnesium and serum potassium prior to starting. (2.5) Optimize glucose control in patients with poorly controlled diabetes mellitus prior to starting. (2.5) Patients with Hepatic Impairment: Child-Pugh B: Recommended initial dose is 20 mg every 4 weeks and maximum dose is 40 mg every 4 weeks (2.4, 8.6) Child-Pugh C: Avoid use in these patients (2.4, 8.6) Follow reconstitution and administration instructions. (2.6) 2.1 Important Administration Instructions SIGNIFOR LAR must be reconstituted by a trained healthcare professional immediately before use. Illustrations on reconstitution are found in Instructions for Use [see Dosage and Administration (2.6)]. SIGNIFOR LAR must be inspected visually before use. The suspension should appear free of foreign particulates and should be homogeneous after mixing. SIGNIFOR LAR must be administered by a trained healthcare professional only by intramuscular injection in the right or left gluteus immediately after reconstitution. SIGNIFOR LAR must never be administered intravenously. 2.2 Recommended Initial Dose The recommended initial dose of SIGNIFOR LAR is 40 mg administered by intramuscular injection once every 4 weeks (every 28 days) [see Dosage and Administration (2.6)]. 2.3 Dose Adjustment and Monitoring The dose may be increased to a maximum of 60 mg for patients who have not normalized growth hormone (GH) and/or age and sex adjusted insulin-like growth factor-1 (IGF-1) levels after 3 months of treatment with SIGNIFOR LAR at 40 mg and who tolerate this dose [see Adverse Reactions (6) and Clinical Studies ( 14)]. Management of SIGNIFOR LAR-related adverse reactions or over-response to treatment (age and sex adjusted IGF-1 less than the lower limit of normal) may require dose reduction. The dose may be decreased, either temporarily or permanently, by 20 mg decrements [see Warnings and Precautions (5)]. 2.4 Dose in Patients with Hepatic Impairment The recommended initial dose for patients with moderately impaired hepatic function (Child-Pugh B) is 20 mg every 4 weeks and the maximum recommended dose is 40 mg every 4 weeks. Avoid use in patients with severe hepatic impairment (Child-Pugh C) [see Use in Specific Populations (8.6)]. 2.5 Recommended Baseline Evaluations Prior to Initiation of SIGNIFOR LAR Prior to the initiation of SIGNIFOR LAR, it is recommended that patients have the following baseline evaluations: Fasting plasma glucose and hemoglobin A1c [see Warnings and Precautions (5.1)] Liver tests [see Warnings and Precautions (5.3)] Electrocardiogram, serum potassium and serum magnesium levels [see Warnings and Precautions (5.2)] Patients with poorly controlled diabetes mellitus who have inadequate glucose control should have antidiabetic therapy optimized prior to starting SIGNIFOR LAR [see Warnings and Precautions (5.1)]. 2.6 Reconstitution and Intramuscular Injection Instructions After reconstitution of the 20 mg, 40 mg, or 60 mg SIGNIFOR LAR vials with the provided 2 mL diluent, the injectable suspension will have a final concentration of 10 mg/mL, 20 mg/mL and 30 mg/mL and should be delivered in its entirety. PAY PARTICULAR ATTENTION: There are 2 critical steps in the reconstitution of SIGNIFOR LAR. Not following these 2 steps could result in failure to deliver the drug appropriately. 1) The injection kit must reach room temperature (see Step 1 in Instructions for Use). Remove the SIGNIFOR LAR injection kit from refrigerated storage and let stand at room temperature for a minimum of 30 minutes before reconstitution, but do not exceed 24 hours. 2) After adding the diluent solution, shake the vial moderately in a horizontal direction for a minimum of 30 seconds until uniform suspension is formed (see Step 4 in Instructions for Use). The following items are included in the injection kit: a) One vial containing SIGNIFOR LAR powder b) One prefilled syringe containing the diluent solution for reconstitution c) One vial adapter for drug product reconstitution d) One safety injection needle (20G x 1.5”) Figure 1: Items Included in Injection Kit SIGNIFOR LAR suspension must only be reconstituted immediately before administration. Follow the directions in the Instructions for Use to ensure proper reconstitution of SIGNIFOR LAR before intramuscular injection. SIGNIFOR LAR should only be administered by a trained healthcare professional. Instructions for Use Step 1 Remove the SIGNIFOR LAR for injectable suspension kit from refrigerated storage. PAY PARTICULAR ATTENTION: It is essential to start the reconstitution process only after the injection kit has reached room temperature. Let the kit stand at room temperature for at least 30 minutes before starting reconstitution, but not more than 24 hours. Note: The kit can be re-refrigerated if needed. Step 2 Remove the plastic cap from the vial and clean the rubber stopper with an alcohol wipe. Remove the lid film of the vial adapter packaging, but do NOT remove the vial adapter from its packaging. Holding the vial adapter packaging, position the vial adapter on top of the vial and push it fully down so that it snaps in place. You will hear an audible “click” when the vial adapter snaps in place. Lift the packaging off the vial adapter with a vertical movement. Step 3 Remove the cap from the syringe prefilled with diluent solution and screw the syringe onto the vial adapter. Slowly push the plunger all the way down to transfer all the diluent solution in the vial. Step 4 ATTENTION: Keep the plunger pressed and shake the vial moderately in a horizontal direction for a minimum of 30 seconds so that the powder is completely suspended. Repeat moderate shaking for another 30 seconds if the powder is not completely suspended. Step 5 Turn the syringe and vial upside down, slowly pull the plunger back and draw the entire content from the vial into the syringe. Unscrew the syringe from the vial adapter. Step 6 Screw the safety injection needle onto the syringe. Pull the protective cover straight off the needle. To avoid sedimentation and maintain a uniform suspension, you may gently shake the syringe. Gently tap the syringe to remove any visible bubbles and expel them from the syringe. The reconstituted SIGNIFOR LAR is now ready for immediate administration. Step 7 SIGNIFOR LAR must only be given by intramuscular injection and NEVER intravenously. Prepare the injection site by wiping with an alcohol wipe. Insert the needle fully into the left or right gluteus at a 90° angle to the skin. Slowly pull back the plunger to check that no blood vessel has been penetrated (reposition if a blood vessel has been penetrated). Slowly depress the plunger until the syringe is empty. Withdraw the needle from the injection site and activate the safety guard (as shown in Step 8). Step 8 Activate the safety guard over the needle using 1 of the 2 methods shown: • either press the hinged section of the safety guard down onto a hard surface (figure A), • or push the hinge forward with your finger (figure B). An audible “click” will confirm proper activation of the safety guard. Dispose of syringe immediately in a sharps container. Any unused product or waste material should be disposed of in accordance with local requirements. Included in the injection kit: Step 1 Step 2 Remove the lid film of the vial adapter packaging, but do NOT remove the vial adapter from its packaging. Lift the packaging off the vial adapter with a vertical movement. Step 3 Slowly push the plunger all the way down to transfer all the diluent solution in the vial. Step 4 Step 5 Unscrew the syringe from the vial adapter. Step 6 Pull the protective cover straight off the needle. Step 7 Step 8 2.7 Missed Dose If a dose is missed and the patient returns prior to the next scheduled dose, a dose may be given up to but no later than 14 days prior to the next dose.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Females and Males of Reproductive Potential: Advise premenopausal females of the potential for an unintended pregnancy (8.3) 8.1 Pregnancy Risk Summary The limited data with SIGNIFOR LAR in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage. In embryofetal development studies in rabbits, findings indicating a developmental delay were observed with subcutaneous administration of pasireotide during organogenesis at doses less than the exposure in humans at the highest recommended dose; maternal toxicity was not observed at this dose [see Data]. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data In embryofetal development studies in rats given 1, 5, and 10 mg/kg/day subcutaneously throughout organogenesis, maternal toxicity was observed at all doses, including the lowest dose tested which had exposures 12 times higher than that at the maximum therapeutic dose based on AUC comparisons across species. An increased incidence of early/total resorptions and malrotated limbs was observed in rats at 10 mg/kg/day. At 10 mg/kg/day in rats, the maternal systemic exposure (AUC) was 42179 ng*hr/mL, approximately 106 times the exposure in humans at the highest recommended dose of 60 mg SIGNIFOR LAR administered as an intramuscular injection once every 4 weeks. In embryofetal development studies in rabbits given 0.05, 1, and 5 mg/kg/day subcutaneously through organogenesis, maternal toxicity was observed at 1 mg/kg/day, at a maternal systemic exposure (AUC) of 1906 ng*hr/mL, approximately 5 times higher than the maximum human therapeutic exposure. An increased incidence of unossified forepaw phalanx, indicative of a developmental retardation, was observed in rabbits at 0.05 mg/kg/day, with maternal systemic exposures less than the systemic exposure in humans at the highest recommended dose. In pre- and post-natal developmental studies in rats given subcutaneous doses of 2, 5, and 10 mg/kg/day during gestation through lactation and weaning, maternal toxicity was observed at all doses including the lowest dose (9 times higher than the maximum therapeutic dose based on surface area comparisons across species). Retardation of physiological growth, attributed to GH inhibition was observed at 2 mg/kg/day during a pre- and post-natal study in rats. After weaning, body weight gains in the rat pups (F1 generation) exposed to pasireotide were comparable to controls, showing reversibility of this developmental delay. 8.2 Lactation Risk Summary There is no information available on the presence of SIGNIFOR LAR in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Studies show that pasireotide administered subcutaneously passes into the milk of lactating rats; however, due to species-specific differences in lactation physiology, animal data may not reliably predict drug levels in human milk [see Data]. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for SIGNIFOR LAR and any potential adverse effects on the breastfed child from SIGNIFOR LAR or from the underlying maternal condition. Data Available data in animals have shown excretion of pasireotide in milk. After a single 1 mg/kg [14C]-pasireotide subcutaneous dose to lactating rats, the transfer of radioactivity into milk was observed. The overall milk:plasma (M/P) exposure ratio of total radioactivity was 0.28, based on AUC0-∞ values. 8.3 Females and Males of Reproductive Potential Discuss the potential for unintended pregnancy with premenopausal women as the therapeutic benefits of a reduction in growth hormone (GH) levels and normalization of insulin-like growth factor (IGF-1) in acromegalic females treated with pasireotide may lead to improved fertility. 8.4 Pediatric Use Safety and effectiveness of SIGNIFOR LAR have not been established in pediatric patients. 8.5 Geriatric Use Clinical studies of SIGNIFOR LAR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment Dose adjustment is not required in patients with mild impaired hepatic function (Child-Pugh A), but is required for patients with moderately impaired hepatic function (Child-Pugh B). The safety and efficacy of SIGNIFOR LAR have not been established in patients with severe hepatic impairment (Child-Pugh C). No dosage recommendation can be given for patients with severe hepatic impairment (Child-Pugh C) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Clinical studies of SIGNIFOR LAR in patients with renal impairment have not been conducted. On the basis of studies with pasireotide given subcutaneously, dosage adjustment is not needed in patients with renal impairment [see Clinical Pharmacology (12.3)].

Interactions

7 DRUG INTERACTIONS Drugs that Prolong QT: Use with caution in patients who are at significant risk of developing QTc prolongation. (5.2, 7.1) Cyclosporine: Consider additional monitoring. (7.2) Bromocriptine: Consider bromocriptine dose reduction. (7.2) 7.1 Effect of Other Drugs on SIGNIFOR LAR Drugs that Prolong QT Coadministration of drugs that prolong the QT interval with SIGNIFOR LAR may have additive effects on the prolongation of the QT interval. Monitor effects on QT interval at 21 days is recommended [see Warnings and Precautions (5.2)]. 7.2 Effect of SIGNIFOR LAR on Other Drugs Cyclosporine Concomitant administration of cyclosporine with SIGNIFOR LAR may decrease the relative bioavailability of cyclosporine and, therefore, dose adjustment of cyclosporine to maintain therapeutic levels may be necessary. Bromocriptine Coadministration of SIGNIFOR LAR with bromocriptine may increase the blood levels of bromocriptine. Dose reduction of bromocriptine may be necessary.

More information

Category Value
Authorisation number NDA203255
Orphan designation No
Product NDC 0078-0641,0078-0643,0078-0642
Date Last Revised 09-03-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 1597822
Marketing authorisation holder Novartis Pharmaceuticals Corporation